Fas and Fas-ligand expression in human pancreatic cancer

Objective To investigate Fas and Fast expression in pancreatic tissues and cultured p ancreatic cancer cell lines, and to assess the ability of anti-fas antibodi es to induce apoptosis. Summary Background Data Activation of the Fas receptor by Fas-ligand (FasL) results in apoptosis, a nd dysregulation of this pathway may contribute to abnormal cell proliferat ion. Methods Northern blotting and immunohistochemistry were used to compare Fas and Fas t expression in normal and cancerous tissues. DNA 3'-OH end labeling was us ed to detect apoptotic cells. The effects of Fas activation on cell growth and signaling pathways were investigated in culture. Results Pancreatic cancers exhibited increased Fas RNA levels, whereas Fast mRNA le vels were similar in both groups. Despite the colocalization of Fas and Fas t in the cancer cells, an apoptotic signal was present in approximately 10% of these cells in only 2 of 16 cancer samples. Fas and Fast were coexpress ed in all four cell lines, whereas Fas-associated phosphatase 1 was below t he level of detection in all cell lines. Only COLO-357 cells underwent apop tosis after Fas activation. Apoptosis was associated with enhanced activati on of jun kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). In the presence of actinomycin D, Fas antibody also induced apoptosis in the o ther three cell lines. Conclusions These results suggest that pancreatic cancer cells are resistant to Fas-med iated apoptosis by mechanisms excluding receptor downregulation or Fas-asso ciated phosphatase upregulation and raise the possibility that Fas-mediated apoptosis may be dependent on the activation of the JNK/p38 MAPK pathway i n these cells.